The menisci are intra-articular fibrocartilaginous structures essential to the normal function of the knee joint. Damage or loss of the menisci often results in progressive osteoarthritic degeneration of the articular cartilage and other joint tissues, leading to significant pain and disability. While the biomechanical contributions of the meniscus to the health of the knee joint are well understood, the biochemical influence of the menisci on joint inflammation is not known. Our prior work has demonstrated that mechanical stress alters the metabolism of menisci, inducing production of nitric oxide (NO) and prostaglandin E2 (PGE2) production. NO and PGE2 production is stimulated by certain cytokines and growth factors, and NO and PGE2 (depending on the rates and sites of production) can serve as pro- or anti-inflammatory molecules. The goal of this study is to determine the influence of these mediators on collagen matrix biosynthesis in the meniscus. We hypothesize that dynamic mechanical stress modifies meniscus collagen mRNA transcription and protein synthesis through pathways that involve NO and PGE2. Furthermore, we hypothesize that certain cytokines act in an additive or synergistic manner with mechanical stress to induce meniscal NO and PGE2 production. We will pursue the following Specific Aims: (1) determine the effects of static and dynamic compression on collagen mRNA expression and protein synthesis in explants of meniscus; (2) determine the role of mechanically-induced NO and PGE2 in regulating collagen synthesis; (3) determine the interaction of mechanical stress with interleukin 1, interleukin 17, and tumor necrosis factor alpha in the production of pro-inflammatory mediators, and (4) determine the interaction between the NO and PGE2 pathways in these regulatory processes. This five-year project brings together a multidisciplinary team with expertise in bioengineering, biology, and rheumatology to study the role of biomechanical factors in mediating inflammation of the meniscus. The long-term goal of these studies is to better understand the mechanisms through which altered mechanical loading of the meniscus influences pain, inflammation, and degeneration of the knee joint. Identification of these mechanisms will hopefully lead to new treatments that exploit optimal mechanical and biochemical modalities for the prevention of disease. [unreadable] [unreadable] [unreadable]